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WO2000038690A2 - Agonistes de prostaglandine e utilises dans le traitement de la keratoconjonctivite seche - Google Patents

Agonistes de prostaglandine e utilises dans le traitement de la keratoconjonctivite seche Download PDF

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Publication number
WO2000038690A2
WO2000038690A2 PCT/US1999/029733 US9929733W WO0038690A2 WO 2000038690 A2 WO2000038690 A2 WO 2000038690A2 US 9929733 W US9929733 W US 9929733W WO 0038690 A2 WO0038690 A2 WO 0038690A2
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WO
WIPO (PCT)
Prior art keywords
alkyl
acyl
proviso
double bond
compound
Prior art date
Application number
PCT/US1999/029733
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English (en)
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WO2000038690A3 (fr
Inventor
Peter G. Klimko
Original Assignee
Alcon Laboratories, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Alcon Laboratories, Inc. filed Critical Alcon Laboratories, Inc.
Priority to AU21838/00A priority Critical patent/AU2183800A/en
Priority to US09/462,719 priority patent/US6462080B1/en
Publication of WO2000038690A2 publication Critical patent/WO2000038690A2/fr
Publication of WO2000038690A3 publication Critical patent/WO2000038690A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids

Definitions

  • the present invention relates to the use of prostaglandin E agonists and partial agonists to stimulate mucin secretion to treat dry eye, keratoconjunctivitis, Sjogren's syndrome and related ocular surface diseases.
  • Dry eye is a common ocular surface disease afflicting millions of people in the U.S. each year, especially the elderly (Schein et. al., Prevalence of dry eye among the elderly. American J. Ophthalmology, 124:723-738, (1997)). Dry eye may afflict an individual with varying severity. In mild cases, a patient may experience burning, a feeling of dryness, and persistent irritation such as is often caused by small bodies lodging between the eye lid and the eye surface. In severe cases, vision may be substantially impaired. Other diseases, such as Sjogren's disease and cicatricial pemphigoid manifest dry eye complications.
  • Practitioners have taken several approaches to the treatment of dry eye.
  • One common approach has been to supplement and stabilize the ocular tear film using so-called artificial tears instilled throughout the day.
  • Another approach has been the use of ocular inserts that provide a tear substitute or to stimulate endogenous tear production.
  • Tear reconstitution is also attempted by providing one or more components of the tear film such as phospholipids and oils.
  • these treatment approaches are disclosed in United States Patent Nos. 4,131,651 (Shah et. al), 4,370,325 (Packman), 4,409,205 (Shively), 4,744,980 and 4,883,658 (Holly), 4,914,088 (Glonek), 5,075,104 (Gressel et. al.) and 5,294,607 (Glonek et. al.).
  • United States Patent No. 5,041,434 discloses the use of sex steroids, such as conjugated estrogens, to treat dry eye condition in post-menopausal women
  • United States Patent No. 5,290,572 discloses the use of finely divided calcium ion compositions to stimulate tear film
  • United States Patent No. 4,966,773 discloses the use of microfine particles of one or more retinoids for ocular tissue normalization.
  • Mucins are proteins which are heavily glycosylated with glucosamine-based moieties. Mucins provide protective and lubricating effects to epithelial cells, especially those of mucosal membranes. Mucins have been shown to be secreted by vesicles and discharged on the surface of the conjuctival epithelium of human eyes (Greiner et. al., Mucus Secretory Vesicles in Conjunctival Epithelial Cells of Wearers of Contact Lenses, Archives of Ophthalmology, 98:1843-1846 (1980); and Dilly et.
  • Mucins are also produced and secreted in other parts of the body including lung airway passages, and more specifically from goblet cells interspersed among tracheal/bronchial epithelial cells. Certain arachidonic acid metabolites have been shown to stimulate mucin production in these cells.
  • Yanni reported the increased secretion of mucosal glycoproteins in rat lung by hydroxyeicosatetraenoic acid ("HETE") derivatives (Yanni et. al, Effect of Intravenously Administered Lipoxygenase Metabolites on Rat Trachael Mucous Gel Layer Thickness, International Archives of Allergy And Applied Immunology, 90:307-309 (1989)).
  • HETE hydroxyeicosatetraenoic acid
  • the conventional treatment for dry eye includes administration of artificial tears to the eye several times a day.
  • Other agents claimed for increasing ocular mucin and/or tear production include vasoactive intestinal polypeptide (Dartt et. al, Vasoactive intestinal peptide-stimulated glycocongjugate secretion from conjunctival goblet cells. Experimental Eye Research, 63:27-34, (1996)) , gefarnate (Nakmura et.
  • Prostaglandins are metabolite derivatives of arachidonic acid. Arachidonic acid in the body is converted to prostaglandin G 2 , which is subsequently converted to prostaglandin H 2 . Other naturally occurring prostaglandins are derivatives of prostaglandin H 2 .
  • a number of different types of prostaglandins are known in the art including A, B, C, D, E, F, G, I and J-Series prostaglandins (US 5151444; EP 0 561 073 Al; Coleman et. al, VIII International Union of Pharmacology classification of prostanoid receptors: Properties, distribution, and structure of the receptors and their subtypes, Pharmacological Reviews, 45:205-229 (1994)).
  • the prostaglandins are further classified with subscripts such as PGD 2 , PGE b PGE 2 , PGF 2 ⁇ , etc.
  • PGD 2 PGE b PGE 2
  • PGF 2 ⁇ PGF 2 ⁇
  • these classes of prostaglandins interact preferably with the designated major classes of receptors (e.g. DP, EP, FP) and subclasses of receptors (e.g.
  • EP 2 , EP 3 , EP 4 the subscripts associated with the prostaglandin does not necessarily correspond with the subclass of the receptor(s) with which they interact. Furthermore, it is well known that these endogenous prostaglandins are non-specific in terms of interacting with the various classes of prostaglandin receptors. Thus, PGE 2 not only interacts with EP 2 receptors, but can also activate EPi, EP 2 , EP 3 and EP 4 receptors (Coleman et. al, VIII International Union of Pharmacology classification of prostanoid receptors: Properties, distribution, and structure of the receptors and their subtypes, Pharmacological Reviews, 45:205-229 (1994)).
  • prostaglandins which are believed to exhibit mucin-producing activity by binding to and activating any of the four recognized prostaglandin E receptors.
  • the present invention is directed to compositions and methods for the treatment of dry eye and other disorders requiring the wetting of the eye. More specifically, the present invention discloses compositions containing prostaglandin E receptor agonists and methods for treating dry eye type disorders.
  • compositions include an effective amount of a prostaglandin E receptor agonist for the production of mucins in mammals, and especially in humans.
  • the compositions are administered topically to the eye for the treatment of dry eye.
  • prostaglandin E receptor agonist refers to any compound which acts as an agonist or partial agonist at one of the prostaglandin EP receptors (EPi, EP 2 , EP 3 , or EP 4 ), thereby stimulating mucin production and/or secretion in the conjunctival epithelium and goblet cells following topical ocular application.
  • prostaglandin EP receptor agonist refers to any compound which acts as an agonist or partial agonist at one of the prostaglandin EP receptors (EPi, EP 2 , EP 3 , or EP 4 ), thereby stimulating mucin production and/or secretion in the conjunctival epithelium and goblet cells following topical ocular application.
  • R 1 (CH 2 ) n CO 2 R, (CH 2 ) n CONR 4 R 5 , (CH 2 ) n CH 2 OR 6 , (CH 2 ) n CH 2 NR 7 R 8 , where:
  • R H or pharmaceutically acceptable cationic salt moiety, or CO 2 R forms a pharmaceutically acceptable ester moiety;
  • R 6 H, acyl, or alkyl
  • n 0 or 2;
  • R 20 C 2 . 8 alkyl, C 2 - 8 alkenyl, aryl, heteroaryl, aryloxy, or heteroaryloxy, optionally substituted with halo, trihalomethyl, OR 3 , NR 3 R 21 .
  • R 3 H, alkyl. or acyl
  • R 21 H, alkyl. or acyl
  • R 9a R 9b 0 as a carbonyl .
  • the individual enantiomers can be enantioselectively synthesized from the appropriate enantiomerically pure or enriched starting material by means such as those described below. Alternatively, they may be enantioselectively synthesized from racemic/non-racemic or achiral starting materials.
  • racemic and non-racemic mixtures may be obtained by several means, including without limitation, nonenantioselective synthesis, partial resolution, or even mixing samples having different enantiomeric ratios. Departures may be made from such details within the scope of the accompanying claims without departing from the principles of the invention and without sacrificing its advantages. Also included within the scope of the present invention are the individual isomers of the disclosed compounds substantially free of their respective enantiomers.
  • ester'V'pharmaceutically acceptable cationic salt means any ester/cationic salt that would be suitable for therapeutic administration to a patient by any conventional means without significant deleterious health consequences; and "ophthalmically acceptable ester'7'Ophthalmically acceptable cationic salt” means any pharmaceutically acceptable ester/cationic salt that would be suitable for ophthalmic application, i.e. non-toxic and non-irritating.
  • Dashed lines on bonds [e.g., between carbons 4 (C-4) and 5 (C-5] indicate a single or double bond. Two solid lines present specify the configuration of the relevant double bond. Hatched lines indicate the ⁇ configuration. A solid triangular line indicates the ⁇ configuration
  • acyl represents a group that is linked by a carbon atom that has a double bond to an oxygen atom and single bond to another carbon atom.
  • acylamino represents a group that is linked by an amino atom that is connected to a carbon atom has a double bond to an oxygen group and a single bond to a carbon atom or hydrogen atom.
  • acyloxy represents a group that is linked by an oxygen atom that is connected to a carbon that has a double bond to an oxygen atom and single bond to another carbon atom.
  • alkenyl includes straight or branched chain hydrocarbon groups having 1 to 15 carbon atoms with at least one carbon-carbon double bond.
  • the chain hydrogens may be substituted with other groups, such as halogen.
  • Preferred straight or branched alkeny groups include, allyl, 1-butenyl, 1 -methyl-2-propenyl and 4-pentenyl.
  • alkoxy represents an alkyl group attached through an oxygen linkage.
  • alkyl includes straight or branched chain aliphatic hydrocarbon groups that are saturated and have 1 to 15 carbon atoms.
  • the alkyl groups may be substituted with other groups, such as halogen, hydroxyl or alkoxy.
  • Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl.
  • alkylamino represents an alkyl group attached through a nitrogen linkage.
  • alkynyl includes straight or branched chain hydrocarbon groups having 1 to 15 carbon atoms with at least one carbon-carbon triple bond.
  • the chain hydrogens may be substituted with other groups, such as halogen.
  • Preferred straight or branched alkynyl groups include, 2-propynyl, 2-butynyl, 3-butynyl, 1 -methyl-2-propynyl and 2- pentynyl.
  • aryl refers to carbon-based rings which are aromatic.
  • the rings may be isolated, such as phenyl, or fused, such as naphthyl.
  • the ring hydrogens may be substituted with other groups, such as lower alkyl, or halogen.
  • carbonyl represents a group that has a carbon atom that has a double bond to an oxygen atom.
  • carbonylalkoxy represents a group that is linked by a carbon atom that has a double bond to an oxygen atom and a single bond to an alkoxy group.
  • carbonyloxyl represents a group that is linked by a carbon atom that has a double bond to an oxygen atom and a single bond to a second oxygen atom.
  • cycloalkyl includes straight or branched chain, saturated or unsaturated aliphatic hydrocarbon groups which connect to form one or more rings, which can be fused or isolated.
  • the rings may be substituted with other groups, such as halogen, hydroxyl or lower alkyl.
  • Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cylopentyl and cyclohexyl.
  • dialkylamino represents two alkyl groups attached through a nitrogen linkage.
  • halogen and "halo” represents fluoro, chloro, bromo, or iodo.
  • heteroaryl refers to aromatic hydrocarbon rings which contain at least one heteroatom such as O, S, or N in the ring. Heteroaryl rings may be isolated, with 5 to 6 ring atoms, or fused, with 8 to 10 atoms. The heteroaryl ring(s) hydrogens or heteroatoms with open valency may be substituted with other groups, such as lower alkyl or halogen.
  • heteroaryl groups include imidazole, pyridine, indole, quinoline, furan, thiophene, pyrrole, tetrahydroquinoline, dihydrobenzofuran, and dihydrobenzindole.
  • lower alkyl represents alkyl groups containing one to six carbons ( - C 6 ).
  • X direct bond
  • R 20 C 2 - 5 alkyl or C 2 - 5 alkenyl, where either is optionally terminated by C 5 - 6 cycloalkyl or C5. 6 cycloalkenyl.
  • R 20 C 2 . 5 alkyl or C 2 - 5 alkenyl, where either is optionally terminated by C 5 . 6 cycloalkyl or C 5 - 6 cycloalkenyl.
  • R a R taken together O as a carbonyl
  • R 20 phenyl, optionally substituted with Cl or CF 3
  • the prostaglandin E agonists of the present invention may be contained in various types of pharmaceutical compositions, in accordance with formulation techniques known to those skilled in the art. In general, these compounds will be formulated in solutions for topical ophthalmic administration. Solutions, suspensions and other dosage forms are particularly preferred for the treatment of dry eye.
  • the ophthalmic compositions of the present invention will include one or more compounds of the present invention in a pharmaceutically acceptable vehicle. Various types of vehicles may be used. Aqueous solutions are generally preferred, based on ease of formulation, biological compatibility, as well as a patient's ability to easily administer such compositions by means of instilling one to two drops of the solutions in the affected eyes.
  • the compounds of the present invention may also be readily incorporated into other types of compositions, such as suspensions, viscous or semi-viscous gels, or other types of solid or semi-solid compositions. Suspensions may be preferred for those compounds of the present invention which are less soluble in water.
  • the ophthalmic compositions of the present invention may also include various other ingredients, such as buffers, preservatives, co-solvents and viscosity building agents.
  • An appropriate buffer system e.g., sodium phosphate, sodium acetate or sodium borate
  • sodium phosphate, sodium acetate or sodium borate may be added to prevent pH drift under storage conditions.
  • Antioxidants may be added to compositions of the present invention to protect the EP 4 agonists from oxidation during storage.
  • antioxidants include vitamin E and analogs thereof, ascorbic acid and butylated hydroxytoluene (BHT).
  • Ophthalmic products are typically packaged in multidose form. Preservatives are thus required to prevent microbial contamination during use. Suitable preservatives include: benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, polyquaternium-1, or other agents known to those skilled in the art. Such preservatives are typically employed at a level of from 0.001 to 1.0% weight/volume ("% w/v").
  • the doses used for the above described purposes will vary, but will be in an effective amount to increase mucin production in the eye and thus eliminate or improve dry eye conditions.
  • the term "pharmaceutically effective amount” refers to an amount which improves the dry eye condition in a human patient.
  • the compositions When the compositions are dosed topically, they will generally be in a concentration range of from 0.001 to about 1.0% w/v, with 1-2 drops administered 1-4 times per day.
  • the term "pharmaceutically acceptable carrier” refers to any vehicle which, when formulated, is safe, and provides the appropriate delivery for the desired route of administration of an effective amount of at least one prostaglandin E agonist of the present invention.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne des compositions et des méthodes de traitement de la kératoconjonctivite sèche et des maladies apparentées chez le mammifère, à l'ade d'agonistes récepteurs de prostaglandine E.
PCT/US1999/029733 1998-12-24 1999-12-14 Agonistes de prostaglandine e utilises dans le traitement de la keratoconjonctivite seche WO2000038690A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU21838/00A AU2183800A (en) 1998-12-24 1999-12-14 Prostaglandin e agonists for treatment of dry eye
US09/462,719 US6462080B1 (en) 1998-12-24 1999-12-14 Prostaglandin E receptor agonists for treatment of dry eye

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US11357498P 1998-12-24 1998-12-24
US60/113,574 1998-12-24

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WO2000038690A2 true WO2000038690A2 (fr) 2000-07-06
WO2000038690A3 WO2000038690A3 (fr) 2000-11-23

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000038663A3 (fr) * 1998-12-24 2000-11-16 Alcon Lab Inc Agonistes du recepteur ep4 utilises dans le traitement du syndrome sec
WO2001005388A3 (fr) * 1999-07-14 2002-05-10 Sucampo Ag Composition destinee au traitement des troubles de la secretion externe
EP2465537A1 (fr) 2002-10-10 2012-06-20 ONO Pharmaceutical Co., Ltd. Promoteurs de production de facteur de réparation endogène
WO2014069401A1 (fr) 2012-10-29 2014-05-08 株式会社カルディオ Agent thérapeutique spécifique de maladie pulmonaire
US9968716B2 (en) 2013-10-15 2018-05-15 Ono Pharmaceutical Co., Ltd. Drug-eluting stent graft

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6586462B2 (en) * 2000-10-20 2003-07-01 Allergan, Inc. ω-Cycloalkyl 17-heteroaryl prostaglandin E2 analogs as EP2-receptor agonists

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000038663A3 (fr) * 1998-12-24 2000-11-16 Alcon Lab Inc Agonistes du recepteur ep4 utilises dans le traitement du syndrome sec
WO2001005388A3 (fr) * 1999-07-14 2002-05-10 Sucampo Ag Composition destinee au traitement des troubles de la secretion externe
US6566398B1 (en) 1999-07-14 2003-05-20 R-Tech Ueno, Ltd. Method for treatment of external secretion disorders
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EP2465537A1 (fr) 2002-10-10 2012-06-20 ONO Pharmaceutical Co., Ltd. Promoteurs de production de facteur de réparation endogène
WO2014069401A1 (fr) 2012-10-29 2014-05-08 株式会社カルディオ Agent thérapeutique spécifique de maladie pulmonaire
US9968716B2 (en) 2013-10-15 2018-05-15 Ono Pharmaceutical Co., Ltd. Drug-eluting stent graft

Also Published As

Publication number Publication date
AU2183800A (en) 2000-07-31
WO2000038690A3 (fr) 2000-11-23
US6462080B1 (en) 2002-10-08

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